Prucalopride (R0-93877) is a potent and specific 5-HT₄ agonist being developed for the treatment of gastrointestinal disorders. The endogenous agonist 5-HT has been shown to increase I_CaL (Ouadid et al., 1992) and induce arrhythmic contractions in human atrium via 5-HT₄ receptors (Sanders et al., 1995). The aim of this study was to assess the effects of prucalopride on functional electrophysiological properties such as L-type Ca²⁺ current (I_CaL), action potential duration (APD), effective refractory period (ERP) and automaticity in human atrial cells and compare these with the effects of 5-HT.

The perforated whole cell patch clamp technique was used in single myocytes isolated enzymatically from the right atrial appendage of patients undergoing cardiac surgery pre-treated with ß-adrenoceptor antagonists. All patients were in sinus rhythm. Cells were continuously superfused with a physiological salt solution at 37±1 °C. Electrodes were filled with a Cs⁺-based solution to eliminate outward K⁺ currents during I_CaL recordings, and a K⁺-based solution was used for action potential recording. I_CaL was measured with repetitive voltage pulses, from -40 to +10 mV and action potentials were stimulated at 75 beats per min with current pulses of 5 ms duration. Data are expressed as mean± standard error of the mean. Values were compared using a two-tailed paired Student's t test, with P<0.05 taken as statistically significant.

Prucalopride (0.001-10 µM, n=6-13 cells from 3-5 patients) produced a concentration-dependent increase in the peak amplitude of I_CaL with a calculated pEC₅₀ of 6.42±0.08 and a Hill coefficient of 0.55±0.04. The maximum effect of prucalopride was observed to occur at around 10 µM (E_max=102±4% above control). After the application of 10 µM prucalopride, 5-HT at 10 µM increased peak I_CaL to 243±38% above control, an increase which was significantly greater than that produced by prucalopride (83±20%; P<0.05, 10 cells). Prucalopride, similarly to 5-HT, increased I_CaL without a change in its voltage dependency. On action potentials, prucalopride (10 µM) (n=6 cells from 5 patients) caused a significant increase in the APD measured at 50% repolarisation (APD₅₀) from 10.9±2.2 ms to 16.2±3.9 ms (P<0.05), that was fully reversible after 3 min washout (11.5±2.7 ms). Following washout, 5-HT (10 µM) increased the APD₅₀ to 29.1±6.0 ms (P<0.05 vs control; P=0.12 vs prucalopride). The APD₉₀ and the ERP were not significantly affected by superfusion with either prucalopride or 5-HT. Prucalopride did not induce spontaneous depolarisations in any of the 6 cells studied whereas 5-HT (10 µM) did in 2 out of 6 cells tested (P=0.12, ² test).

In conclusion, in human atrial cells prucalopride, at concentrations markedly (> 400 times) above those used therapeutI_CaLly, exhibits similar effects to 5-HT on calcium current, early and late repolarisation and refractory period but acts as a partial rather than a full agonist.

Ouadid H. et al. (1992) Mol. Pharmacol. 41: 346-351.
Sanders L. et al. (1995) Circulation 92: 2526-2539.

Supported by Johnson & Johnson PharmaceutI_CaL Research and Development.